Project 3. Translational Clinical Trials for Primary CMSTumors. David A. Reardon, M.D., Project Leader Despite standard post-surgical cytotoxic radiotherapy and chemotherapy, the outcome for patients with primary brain tumors remains dismal. To overcome the limitations of conventional approaches, we have developed innovative therapeutics including a peptide vaccine against the tumor-specific EGFRvlll mutant receptor and a regionally administered, radiolabeled anti-tenascin monoclonal antibody, that have each advanced to multi-center, randomized phase III studies based on highly encouraging improved survival and minimal toxicity observed in clinical trials conducted at our center. In this application, we will further advance these approaches by expanding our immunotherapy program to: evaluate dose intensive temozolomide or bevacizumab to enhance EGFRvlll vaccine immunogenicity;evaluate our EGFRvlll vaccine among patients with non-resectable tumors;and evaluate a novel brain tumor stem cell RNA-pulsed dendritic cell vaccination strategy. We will also evaluate several tumor-specific MAb immunotoxin constructs developed and extensively evaluated preclinically at our center that target EGFRvlll (MR1-1;BB-IND# 12589), wild-type EGFR and EGFRvlll (D2C7), glycoprotein non-metastatic B (F6V), gangliosides 3'-isoLM1 and 3'6'-isoLD1, and chondroitin proteoglycan sulfate (Me1-14, Me1-5, and 9.2.27), respectively. We will also evaluate three novel, regionally administered therapeutic strategies including Auger electron-labeled modular recombinant transporters (MRT) against EGFR (Project 1), a recombinant poliovirus/rhinovirus construct produced through the NCI RAID program, and a novel balloon catheter device for convection enhanced delivery (CED). Finally, we will also investigate potential limitations of CED by co-infusing a radiolabeled high molecular weight marker such as 124l-albumin imaged by positron emission tomography. We hypothesize that innovative therapeutics, appropriate clinical trial eligibility, rigorous target validation, and enhanced delivery strategies will improve overall survival and quality of life for patients with malignant glioma. Our Specific Aims are: 1. To conduct Phase I and II clinical trials to assess whether innovative therapeutics including vaccine immunotherapy strategies, novel immunotoxins, modular recombinant transporters and genetically modified poliovirus, can improve overall survival and quality of life for malignant glioma patients; 2. To conduct Phase I and II clinical trials designed to determine whether enhanced local delivery of novel therapeutics can be achieved in order to improve overall survival and quality of life for malignant glioma patients. RELEVANCE (See instructions): The clinical investigation studies in Project 3 are all designed to develop more effective and less toxic treatments for malignant brain tumors.